Benzo [c] quinolizine derivatives, their preparation and use as 5alpha-reductases inhibitors

ABSTRACT

The present invention refers to benzo[c]quinolizine derivatives of general formula (I)  
                 
 
     their pharmaceutically acceptable salts or esters, processes for their preparation and pharmaceutical compositions containing them.

FIELD OF THE INVENTION

[0001] The present invention refers to benzo[c]quinolizine derivativesof general formula (I)

[0002] wherein:

[0003] R₁, R₂, R₃, R₄, R₆, same or different, are chosen in the groupconsisting of: H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkinyl, cycloalkyl, aryl,heterocycle, halogen, CN, azide, NRR′, C₁₋₈alkylamino, arylamino,C₁₋₈alkyloxy, aryloxy, COOR, CONRR′ wherein R and R′, same or different,are chosen in the group consisting of: H, C₁₋₈alkyl, cycloalkyl, aryl,heterocycle, arylC₁₋₈alkyl;

[0004] R₅ is chosen in the group consisting of: H, C₁₋₈alkyl, COOR, CN,aryl, heterocycle;

[0005] X is chosen in the group consisting of: O, C(═O)R, COOR, NO₂,CONR'R wherein R and R′ are as above defined;

[0006] Q is chosen in the group consisting of: simple bond, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkinyl, cycloalkyl, CO, CONR, NR, wherein R is asabove defined;

[0007] W is chosen in the group consisting of: H, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkinyl, cycloalkyl, trifluoromethyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, arylC₁₋₈alkyl, aryl, aryloxy, arylamino,C₁₋₈alkylcarbonyl, arylcarbonyl, halogen, CN, NRR′, C₁₋₈alkylamino,heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl,aryl, heterocycle, can be substituted;

[0008] n is an integer comprised between 1 and 4; the symbol ------means that the corresponding bonds a, b, c, d e, f, and g can be simpleor double bonds;

[0009] with the proviso that when b or f are a double bond then thegroup R₅ is absent; and with the proviso that the following twocompounds are excluded:4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizin-3-one and3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one;

[0010] their pharmaceutically acceptable salts or esters, their processfor preparation and their use as inhibitors of steroid 5alpha-reductases(hereinafter indicated as 5alpha-reductases).

[0011] The invention refers also to compounds of formula (4)

[0012] wherein W, Q, n, R₃, R₄, R₅ are as above defined and Z is aprotecting group for the amide-group with the proviso that whenR₃=R₄=R₅=(WQ)_(n)=H than Z is not a group ethoxycarbonyl.

STATE OF THE ART

[0013] The enzyme known as steroid 5alpha-reductase is a system formedby two iso-enzymes (type I and type II or 5alphaR-I and 5alphaR-IIrespectively)) which converts testosterone into dihydrotestosterone, themost powerful androgen circulating in the body.

[0014] The type I iso-enzyme (5alphaR-I) is mainly present in liver andskin while the type II iso-enzyme (5alphaR-II) is mainly present in theprostate tissue and in the male sexual organs and its activity isessential in the fetal developping process for the differentiation ofthe external sexual organs.

[0015] The production of dihydrotestosterone is associated with somepathologies which are widely diffused as for example benign prostatehypertrophy, prostate cancer, baldness and acne in men and hirsutism inwomen. More particularly iso-enzyme I plays a role in the pathologiesregarding the skin while iso-enzyme-II is involved in prostatepathologies.

[0016] In the recent years a lot of international searchers have triedto isolate new compounds capable of inhibiting the 5α-reductase enzymein order to treat the above said pathologies, especially, if possible,acting selectively on only one of the two iso-enzymes.

[0017] Inhibitors of 5α-reductase, and also of the iso-enzymes 5αR-I and5αR-II were already described, for example finasteride used with successin the treatment of benign prostate hypertrophy [see for exampleJ.Med.Chem. 36, 4313-15 (1993), J.Med.Chem. 37, 3871-74 (1994)]. It istherefore evident the importance of developing new compounds capable ofinhibiting the action of the 5α-reductase enzyme and in particularcapable of acting selectively on 5αR-I iso-enzyme which, as said, isresponsible, of widely diffused pathologies having an high impact asbaldness in men and hirsutism in women.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention refers to new compounds capable ofinhibiting the 5α-reductase enzyme, either selectively in respect of5αR-I and 5αR-II or on both the iso-enzymes, useful for the treatment ofthe pathologies mediated by the enzyme.

[0019] The products according to the invention have general formula (I)

[0020] wherein the substituents R₁, R₂, R₃, R₄, R₅, R₆, X, Q, W, n andthe symbol ----- are as above defined.

[0021] According to the present invention with group C₁₋₈alkyl,C₂₋₈alkenyl and C₂₋₈alkinyl are indicated linear or branched alkylradicals as for example: methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl, heptyl, octyl, ethylene, propene, butene, isobutene,acetylene, propine, butine ecc.

[0022] With cycloalkyl are indicated: cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane,canphane, adamantane.

[0023] With aryl are indicated: phenyl and naphtyl. Heterocycle means inparticular: saturated or aromatic heterocycles containing one or more Natoms, more particularly: piridine, imidazole, pyrrole, indole,triazoles, pyrrolidine, piperidine. Halogen means: fluorine, chlorine,bromine, iodine.

[0024] The substituents of the above said group W are preferably:halogen, OR, phenyl, NRR′, CN, COOR, CONRR′, C₁₋₈alkyl (wherein R and R′are as above defined).

[0025] In particular, according to the present invention compounds offormula (I) are preferred wherein:

[0026] R₅=H, heterocycle

[0027] X═O

[0028] Q=simple bond, CO, CONR, NR (wherein R is as above defined) W=H,F, Cl, Br, Me, t-butyl, C₁₋₈alkoxy, 2,5-dimethylhexyl, trifluoromethyl,2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl,phenyl, phenyl-C₁₋₈alkyl, C₁₋₈alkylcarbonyl, phenylcarbonyl.

[0029] n=1 and 2

[0030] R₁, R₂, R₃, R₄, R₆=H, Me, CN, phenyl, COOR, CONRR′ (wherein R andR′ are as above defined).

[0031] Among the pharmaceutically acceptable esters and salts accordingto the present invention the following can be mentioned: hydrochloride,sulphate, citrate, formiate, phosphate.

[0032] Preferred compounds according to the present invention are:

[0033] 1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;

[0034] 8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;

[0035] 1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one;

[0036] 1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one;

[0037] 1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one;

[0038] 1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0039] 8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0040] 8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0041] 4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0042] 1-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0043] 4,4a,5,6 tetrahydro-(11H) -benzo[c]quinolizine-3-one;

[0044] 5,6-dihydro- (11H)-benzo[c]quinolizine-3-one;

[0045] 8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0046] 8-chloro-1-methyl-4,4a,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0047] 8-methyl-4,4a, 5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0048] 4-methyl-4,4a,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis)and (trans);

[0049] 8-chloro-4-methyl-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0050] 4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;

[0051] 4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one(cis) and (trans);

[0052]8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one(cis) and (trans).

[0053] The compounds according to the present invention can be preparedfor example starting from compounds of formula 2

[0054] (2)

[0055] wherein R₃, R₄, W, Q and n are as above defined, following thereaction Scheme reported hereinafter.

[0056] The compounds 2 are commercialy available or can be preparedaccording to known techniques.

[0057] As it can be seen from the Scheme the preparation of thecompounds according to the invention involves the protection of theamide-group in compound 2 by the protecting group Z, for exampletert-butoxycarbonyl (t-Boc), to give compound 3; compound 3 is reducedto compound 4, for example (when R₅ is H) with sodium borohydride inethanol (pH 3), which is reacted with a silylether 6, produced “in situ”starting from vinyl-ketones 5 (wherein R₁, R₂ and R₆ are as abovedefined) with a silylating agent astrimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and thereafterhydrolized, for example in sodium hydrogencarbonate, to give thecompounds of formula (I) wherein X=0. The possible introduction of thedouble bonds and the transformation of the group X in one of the othergroups mentioned above can be easily performed according to knowntechniques starting from the corresponding compound of formula (I)obtained as indicated. For example the introduction of the double bondsin position a or b, can be performed by reaction ofdichlorodicyanoquinone (DDQ) with the corresponding silylenolethers orby oxidation with mercuric acetate of the saturated correspondingcompound obtained as described above. The transformation of group X canbe performed via the corresponding enoltriflates and their carbonylationin the presence of palladium diacetate, triphenylphosphine and thesuitable nucleophilic reagent (alcohol, amine, nitro-group).

EXAMPLE 1 Preparation ofN-(t-butoxycarbonyl)-3,4-dihydroquinolin-2(1H)-one [compound 3 wherein(QW)_(n)—H, R₃—R₄—H]

[0058] 5 g (34 mmoles) of 3,4-dihydroquinolin-2(1H)-one [compound 2wherein (QW)₂═H, R₃═R₄═H] and 111 ml of CH₂Cl₂ are charged, undernitrogen, in a 250 ml round bottom flask, equipped with magneticstirrer.

[0059] To the above said mixture 4.7 ml (34 mmoles) of triethylamine(distilled on KOH), 8.9 g (40.8 mmoles) of di-butyl dicarbonate and 1 g(8.2 mmoles) of 4-dimethylaminopyridine are added. The mixture isstirred under reflux for 5 h, then for one night at room temperature andthereafter the solvent is removed and 200 ml of water are added. Theaqueous phase is extracted with diethylether and the organic phase isneutralized with an aqueous solution of KHSO₄ (1 M). The organic phaseis washed with a saturated solution of NaCl and dried on Na₂SO₄. Afterfiltration and removal of the solvent 8.23 g of the desired product areobtained (white crystals). M.p.: 68-69° C. Yield: 98%.

EXAMPLE 2 Preparation ofN-(t-butoxycarbonyl)-2-ethoxy-1,2,3,4-tetrahydroquinoline [compound 4wherein (QW)_(n)═H, R₃═R₄═R₅═H].

[0060] 4.35 g (17.6 mmoles) of the compound obtained from example 1 and136 ml of absolute ethanol are charged in a 500 ml round bottom flaskequipped with magnetic stirrer.

[0061] The solution is cooled at −25° C. and 2.66 g (70.4 mmoles) ofNaBH₄ (subdivided in 6 portions) are added to the mixture in 1 h. After4 h a solution of HCl 2N in absolute ethanol is added to the mixture, upto pH 3, and the mixture is stirred at 0° C. for 1,5 h. 100 ml of waterare added, the aqueous phase is extracted with methylene chloride, theorganic phase is washed with a saturated solution of NaHCO₃ and asaturated solution of NaCl and the mixture is dried on Na₂SO₄. Afterfiltration the solvent is removed and 4,74 g of the expected product areobtained (dense yellow liquid); yield 96%.

[0062] Operating as above said other compounds 4 wherein thesubstituents can not be reduced by NaBH4 are obtained; if substituentswhich could be reduced by NaBH4 are present these must be previouslyprotected.

EXAMPLE 3 Preparation of1,2,4,4a,5,6-hexahydro-(11H)-benzo[c]quinolizin-3-one [compound offormula (I) wherein X═0; (QW)_(n)═H; R₁═R₂═R₃═R₄═R₅═R₆═H;a,b,c,e,f,g=simple bond]

[0063] 70 μl (0.86 mmoles) of 3-buten-2-one [compound of formula 5wherein R₁═R₂═R₆═H] and 2 ml of anhydrous CH₂Cl₂ are charged, at 0° C.under argon in a two-necked round bottom flask equipped with magneticstirrer and dropping funnel. 170 μl (1.22 mmoles) of triethylamine(distilled on KOH) and 209 μl (1.08 mmoles) oftrimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are addedto the mixture. In this conditions 2-(trimethylsilyloxy)-1,3-butadiene[compound 6 wherein R₁ =R₂═R₆═H] is formed “in situ”. The mixture isstirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles)of the product from Example 2 in 2 ml of anhydrous CH₂Cl₂ is addedtherein, drop by drop, together with 69 μl (0.36 mmoles) of TMSOTf. Themixture is brought to room temperature and after 30 minutes 4 ml of asaturated solution of NAHCO₃ are added and the mixture is stirredvigorously for 36 h.

[0064] 4 ml of water are added to the mixture and the aqueous phase isextracted with methylene chloride, the organic phase is washed with asaturated solution of NaHCO₃, water, a saturated solution of NaCl and isdried on Na₂SO₄. After filtration the solvent is removed and 59 mg ofcrude product are obtained. The product is purified by flashchromatography on silica gel column (FCC) eluting with methylenechloride and triethylamine 1%. 18 mg of the wanted product are obtained(crystals). M.p.: 53-54° C. Yield 25%.

[0065] Using various vinyl-ketones 5, or using directly the varioussilylenolethers 6 (when available), it is possible to prepare thecorresponding derivatives of formula (I).

[0066] In particular when 1-methoxy-3-(trimethylsilyloxy)-1-3-butadiene(compound 6 wherein R₁═MeO, R₂═H, R₆═H) was used,4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizin-3-one (compound I whereinX═O, (QW)_(n)═H, R₁═R₂═R₃═R₄═R₅═R₆═H, a=double bond; b,c,e,f,g=singlebond] was directly obtained according to the synthesis described in thefollowing Example 4.

EXAMPLE 4 Preparation of4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizin-3-one [compound I whereinX═O, (QW)_(n)═H; R₁═R₂═R₃═R₄═R₅═R₆═H a=double bond; b,c,e,f,g=singlebond].

[0067] To a stirred solution of compound 4 [(QW)_(n)═H, R₃═R₄═H] (4 g,14.42 mmol) of the example 3, in 75 ml of anhydrous CH₂Cl₂ under argonat −10° C. is added, dropwise in 7 min, 28.84 ml of a 1M solution ofTiCl₄ in CH₂Cl₂ maintaining the temperature below −5° C. Then1-methoxy-3-(trimethylsilyloxy)-1-3-butadiene (compound 6, R₁═MeO, R₂═H,R₆═H) (3.29 ml, 17.3 mmol) is added by syringe at 0° C., and thereaction was left aside at room temperature for 1 h. The reactionmixture is added, cautiously, with 100 ml of NaHCO satured solution, andthen stirred for 30 min. The organic layer is separated, washed withwater, filtered on Celite and dried over Na₂SO₄. After removal of thesolvent the crude product is purified by flash column chromatography(eluant light-petroleum ether/ethyl acetate 1:4) affording 0.72 g (25%yield) of the expected product (white crystals, m.p.: 135-137° C.).

EXAMPLE 5

[0068] a) Preparation of4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compoundof formula (I) wherein X═O; (QW)_(n)═H; R₁═R₃═R₄═R₅═R₆═H; R₂═Me;a=double bond; b,c,e,f,g=single bonds],4-methyl-1,2,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound offormula (I) wherein X═O; (QW)_(n)═H; R₁═R₃═R₄═R₆═H; R₂═Me; b=doublebond; a,c,e,f,g=single bonds] and4-methyl-5,6-dihydro-(11H)-benzo[c]quinolizine-3-one [compound offormula (I) wherein X═O; (QW)₂═H; R₁═R₃═R₄═R₆═H; R₂═Me; a,b=doublebonds; c,e,f,g=single bonds].

[0069] 1 g (4.64 mmol) of4-methyl-1,2,4,4a,5,6-hexahydro-(11H)-benzo[c]quinolizine-3-one[compound of formula (I), wherein X═O: (QW)_(n)═H; R ₁═R₃═R₄═R₅═R₆═H;R₂═Me; a,b,c,e,f,g=single bonds, obtained according to example 3 byreaction of compound 4 (wherein (QW)_(n)═H; R₃═R₄═R₅═H) of example 2 andethylvinylketone (compound 5 wherein R₁═R₆═H; R₂═Me] and 120 ml of 5%solution (v/v) of glacial acetic acid in water are charged undernitrogen in a two-necked round bottom flask, equipped with magneticstirrer, refrigerator and dropping funnel. Under vigorous stirring, 7.27g (18.56 mmol) of tetrasodic salt EDTA and 5.92 g (18.56 mmol) of(CH₃CO₂)₂Hg are added and the reaction mixture is heated at 90° C. for 2h. After cooling at room temperature the reaction mixture is added with120 ml of water and extracted with methylene chloride (4×70 ml). Theseparated organic phase is washed with a satured solution of NaHCO₃,with a satured solution of NaCl then dried over Na₂SO₄. After removal ofthe solvent the crude product is purified by flash chromatography onsilica gel by elution with ethylacetate/light petroleum ether 2:1affording:

[0070] 83 mg (10%) (gummy solid) ofcis-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one[compound of formula (I) wherein X═O: (QW)_(n)═H; R₁═R₃═R₄═R₅═R₆═H;R₂═Me; a=double bond; b,c,e,f,g=single bonds]

[0071] 350 mg (40%) (crystals, m.p.: 148-150° C.) of 4methyl-1,2,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound offormula (I) wherein X═O: (QW)_(n)═H; R₁═R₃═R₄═R₆═H; R₂═Me; b=doublebond; a,c,e,f,g=single bonds] and

[0072] 107 mg (12%) (gummy solid) of4-methyl-5,6-dihydro-(11H)-benzo[c]quinolizine-3-one [compound offormula (I) wherein X═O: (QW)_(n)═H; R1═R₃═R₄═R₆═H; R₂═Me; a,b=doublebonds; c,e,f,g=single bonds].

Activity Test

[0073] The inhibition potency of the prepared compounds in respect ofthe iso-enzymes 1 and 2 of 5α-reductase was determined using tissuesamples (for example prostate human tissue) or human cellular systems(for example DU 145 cells) expressing iso-enzymes 2 and 1 respectively.

[0074] The samples are incubated in the presence of testosteronelabelled with tritium and thereafter the quantity of labelleddihydrotestosterone formed in the absence and in the presence of theinhibitor is measured.

[0075] The compounds showed high inhibiting power of 5α-reductase enzyme(in particular of iso-enzyme 1) with an inhibition higher than 50% atthe concentration of 10-100 nM.

[0076] For the therapeutical administration the compounds according tothe invention are prepared in the form of pharmaceutical compositionscontaining the active principle and the organic or inorganic excipientssuitable for the oral, parenteral or topic administration of thecompositions. The pharmaceutical compositions can therefore be in thesolid form (dragees, suppositories, creams, ointments), liquid form(solutions, suspensions, emulsions) and can possibly contain thestabilizers, conservatives, humectants, emulsifier, buffers or saltsused for equilibrating the osmotic pressure which are commonly used inthe art.

[0077] Generally the administration of the compounds is performedaccording to the modalities and quantities observed for the known agentsused for the same purposes and taking into consideration the age andconditions of the patients.

1. Benzo[c]-quinolizine compounds of formula (I)

wherein R₁, R₂, R₃, R₄, R₆, same or different, are chosen in the groupconsisting of: H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkinyl, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromaticheterocycle containing one or more N atoms, halogen, CN, azide, NRR′,C₁₋₈alkylamino, arylamino, C₁₋₈alkyloxy, aryloxy, COOR, CONRR′ wherein Rand R′, same or different, are chosen in the group consisting of: H,C₁₋₈alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl,naphtyl, saturated or aromatic heterocycle containing one or more Natoms, arylCl₈alkyl; R₅ is chosen in the group consisting of: H,C₁₋₈alkyl, COOR, CN, phenyl, naphtyl, saturated or aromatic heterocyclecontaining one or more N atoms; X is chosen in the group consisting of:O, C(═O)R, COOR, NO₂, CONR'R wherein R and R′ are as above defined; Q ischosen in the group consisting of: simple bond, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, CO, CONR,NR, wherein R is as above defined; W is chosen in the group consistingof: H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkinyl, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane,canphane, adamantane, trifluoromethyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,arylC₁₋₈alkyl, phenyl, naphtyl aryloxy, arylamino, C₁₋₈alkylcarbonyl,arylcarbonyl, halogen, CN, NRR′, C₁₋₈alkylamino, saturated or aromaticheterocycle containing one or more N atoms, wherein the groups alkyl,alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl,naphtyl, saturated or aromatic heterocycle containing one or more Natoms can be substituted by halogen, OR, phenyl, NRR′, CN, COOR, CONRR′,C₁₋₈alkyl (wherein R and R′ are as above defined); n is an integercomprised between 1 and 4; the symbol ------ means that thecorresponding bonds a, b, c, d e, f, and g can be simple or doublebonds; with the proviso that when b or f are a double bond then thegroup R₅ is absent; and with the proviso that the following twocompounds are excluded from the claim:4-carbonitril-2,3-dihydro-(11H)-benzo[c]quinolizin-3-one and3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one; theirpharmaceutically acceptable salts or esters.
 2. Benzo[c]-quinolizinecompounds of formula (I) according to claim 1 wherein R₅═H, saturated oraromatic heterocycle containing one or more N atoms; X═O: Q═simple bond,CO, CONR, NR (wherein R is as above defined); W═H, F, Cl, Br, Me,t-butyl, C₁₋₈alkoxy, 2,5-dimethylhexyl, trifluoromethyl,2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl,phenyl, phenyl-C₁₋₈alkyl, C₁₋₈alkylcarbonyl, phenylcarbonyl; n═1 and 2;R₁, R₂, R₃, R₄, R₅, R₆═H, Me, CN, phenyl, COOR, CONRR′ (wherein R and R′are as above defined).
 3. Benzo[c]-quinolizine compounds according toclaim 1 of formula 1,2,4,4a,5,6hexahydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-1,2,4,4a,5,6hexahydro-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,5,6tetrahydro-(11H) -benzo[c]quinolizine-3-one; 8-chloro-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 8-methyl-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4-methyl-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 1-methyl-1,2,4,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4,4a,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 5,6-dihydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-4,4a ,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one;8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H) -benzo[c]quinolizine-3-one;8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and(trans); 8-chloro-4-methyl-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4,8-dimethyl-1,2,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4,8-dimethyl-4,4a,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one(cis) and (trans).
 4. Process for the preparation of compounds accordingto claim 1 wherein: the amide-group of a compound of formula (2)

 is protected with a protecting group Z to give the compound (3)

 the above said compound (3) is reduced to compound (4), for examplewith sodium borohydride in ethanol (pH3)

 (4) and compound (4) is reacted with a silylether (6)

 (6) p1 prepared “in situ” by reacting a vinyl-ketone (5)

(5) (wherein R₁, R₂, R₆ are as above defined) with a silylating agent astrimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and are finallyhydrolized, for example with sodium hydrogencarbonate, to give the finalcompound of formula (I) wherein X═O.
 5. Process according to claim 4wherein the possible introduction of the double bonds in position a or bis performed by reaction of dichlorodicianoquinone (DDQ) with thecorresponding silylenolethers or by oxidation with quicksilver acetateof the saturated compound obtained as claimed above and the possibletransformation of the group X is performed via the correspondingenoltriflates and following carbonylation in the presence of palladiumdiacetate, triphenylphosphine and the suitable nucleophilic reagent. 6.Compound of formula (4)

 (4) wherein W, Q, n, R₃, R₄, R₅ are as defined in claim 1 and Z is aprotecting group for the amide-group with the proviso that whenR₃═R₄═R₅═(WQ)_(n)═H than Z is not a group ethoxycarbonyl. 7.Pharmaceutical composition wherein the active principle is a compound offormula (I)

 wherein: R₁, R₂, R₃, R₄, R₆, same or different, are chosen in the groupconsisting of: H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkinyl, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromaticheterocycle containing one or more N atoms, halogen, CN, azide, NRR′,C₁₋₈alkylamino, arylamino, C₁₋₈alkyloxy, aryloxy, COOR, CONRR′ wherein Rand R′, same or different, are chosen in the group consisting of: H,C₁₋₈alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl,naphtyl, saturated or aromatic heterocycle containing one or more Natoms arylC₁₋₈alkyl; R₅ is chosen in the group consisting of: H,C₁₋₈alkyl, COOR, CN, phenyl, naphtyl, saturated or aromatic heterocyclecontaining one or more N atoms; X is chosen in the group consisting of:O, C(═O)R, COOR, NO₂, CONR'R wherein R and R′ are as above defined; Q ischosen in the group consisting of: simple bond, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, CO, CONR,NR, wherein R is as above defined; W is chosen in the group consistingof: H, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈alkinyl, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane,canphane, adamantane, trifluoromethyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,arylC₁₋₈alkyl, phenyl, naphtyl, aryloxy, arylamino, C₁₋₈alkylcarbonyl,arylcarbonyl, halogen, CN, NRR′, C₁₋₈alkylamino, saturated or aromaticheterocycle containing one or more N atoms wherein the groups alkyl,alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl,naphtyl, saturated or aromatic heterocycle containing one or more Natoms can be substitued by halogen, OR, phenyl, NRR′, CN, COOR, CONRR′,C₁₋₈alkyl (wherein R and R′ are as above defined); n is an integercomprised between 1 and 4; the symbol ------ means that thecorresponding bonds a, b, c, d e, f, and g can be simple or doublebonds; with the proviso that when b or f are a double bond then thegroup R₅ is absent; their pharmaceutically acceptable salts or esters ormixtures thereof in combination with the suitable pharmaceuticalacceptable excipients.
 8. Pharmaceutical composition according to claim7 for use in the inhibition of the 5alphaR-I and/or 5alphaR-IIiso-emzymes.
 9. Pharmaceutical composition according to claims 7 and 8in the form suitable for topic use.
 10. Use of a compound of formula (I)according to claim 7 as a medicament.
 11. Use of a compound of formula(I) according to claim 7 for the preparation of a pharmaceuticalcomposition for the treatment of acne, baldness, prostatic cancer andprostatic hypertrophy in men and hirsutism in women.
 12. Method for thetreatment of pathologies related to 5alpha-reductase enzymes byadministration to the patient of a pharmaceutically active amount of apharmaceutical composition according to claims
 7. 13. Method fortreatment of acne, baldness, prostatic cancer and prostatic hypertrophyin men and hirsutism in women, by administration of a pharmaceuticallyactive amount of a pharmaceutical composition according to claims 7.